Frequent alterations of hMLH1 and RBSP3/HYA22 at chromosomal 3p22.3 region in early and late‐onset breast carcinoma: clinical and prognostic significance

Abstract

Young age can be an independent prognostic factor for adverse prognosis in women with breast carcinoma (BC). In younger women, BC exhibited more aggressive pathological features than older women, indicating differences in biology. Frequent alterations in chromosomal (chr.) 3p22.3 in different malignancies indicated the existence of multiple candidate tumor suppressor genes (TSG) in this region, yet its association with BC remains unclear. In an effort to understand the differences in molecular pathogenesis in two age groups of BC, detailed analysis of alterations at chr.3p22.3 region was carried out in 47 early onset (group-A: 40 years) and 59 lateonset (group-A: >40 years) BC samples. Deletion mapping of the four candidate TSG, hMLH1, APRG1, ITGA9 and RBSP3/HYA22, located within 1 Mb of chr.3p22.3 showed high deletion in hMLH1 and RBSP3/HYA22 genes. Frequent methylation was also observed in these genes and significantly associated with their deletion. Quantitative messenger RNA (mRNA) expression and immunohistochemical analysis showed down-regulation of these genes. Alterations (deletion/methylation) of hMLH1 were significantly associated with RBSP3/HYA22 in group-A (P = 0.02). Significant poor survival in group-A patients with alterations in hMLH1 and RBSP3/ HYA22 and the same in group-B patients with hMLH1 alterations indicated their importance as prognostic markers. Differential association of alterations of these genes with higher histological grades, more advanced stages and positive lymph node involvement were also seen. Thus, the present study suggests hMLH1 and RBSP3/HYA22 to be candidate TSG associated with development of both early and late-onset BC undergoing frequent genetic and epigenetic alteration and having significant prognostic implications. (Cancer Sci 2008; 99: 1984-1991 B reast cancer (BC), is the third most prevalent malignancy and primary cause of death in women worldwide.(1) In India, it accounts for 19% of all cancers among women, and is the second most common cancer when both sexes are considered together, whereas about 23% of eastern Indian women suffer from this disease. (2,3) Considering the age at onset of tumor, BC can be classified as early onset (group-A: ≤40 years) and late-onset (group-B: >40 years).(4,5) However, the cut-off value for early onset BC varies among investigators, ranging from 35-50 years. (6,7) Despite this discrepancy, younger women with BC exhibit more aggressive pathological features, including large tumor size of higher grade, presence of positive lymph nodes, absence of steroid receptors and high S-phase fraction, than older women with BC.(6,7) Another report showed that, in an Asian population, BC patients below 40 years have tumors with a poorer prognostic profile. However, this did not translate into poorer overall survival and might be attributable to more aggressive adjuvant treatment of younger patients.(8) All these reports suggested early onset BC to be a biologically separate disease that independently predicts more adverse outcomes. Thus, the mol...

RBSP3 is frequently altered in premalignant cervical lesions: Clinical and prognostic significance

“…However, before this study, no one has investigated the alterations of this gene in more than 100 samples. As yet, no one has reported methylation of RBSP3 in CACX, though a similar report exists for breast cancer (Sinha et al, 2008). Deregulation of the normal splicing patterns of RBSP3 pre-mRNA, like that of many cancerrelated genes, e.g., CD44 and WT1 (Brinkman, 2004), represents an inactivating mechanism for RBSP3.…”

Loss of SNAIL Regulated miR-128-2 on Chromosome 3p22.3 Targets Multiple Stem Cell Factors to Promote Transformation of Mammary Epithelial Cells

“…1B). The 21-kDa cAMP-regulated phosphoprotein (ARPP21), also known as Regulator of Calmodulin Signaling, which is enriched in brain, has been described as a candidate TSG and is frequently deleted in mammary carcinoma (16). We first detected the expression of ARPP21 using quantitative reverse transcription (qRT)-PCR and observed a significant reduction in breast cancer (n ¼ 21) compared with normal specimens (n ¼ 15; Fig.…”

CTDSPL (CTD (Carboxy-Terminal Domain, RNA Polymerase II, Polypeptide A) Small Phosphatase-Like)

“…-High deletion (30%, 24% cases) and methylation (38%, 32% cases) were observed in Groups A and B respectively (Sinha et al, 2008). -28.9 ± 39.1 fold reduction in expression of RBSP3 was observed in about 33 -40% of the tumors (Sinha et al, 2008). …”

“…Prognosis Patients belonging lower to age of onset (≤40 yrs) with alterations of RBSP3 had poor disease outcome (Sinha et al, 2008). Oncogenesis Higher alterations of RBSP3 were observed in patients belonging to the lower age of onset (Group A) (Sinha et al, 2008).…”

“…Note -Study population was divided into two groups, Group A (≤40 yrs, early onset) and Group B (>40 yrs, late onset) (Sinha et al, 2008). -High deletion (30%, 24% cases) and methylation (38%, 32% cases) were observed in Groups A and B respectively (Sinha et al, 2008).…”